Agnieszka K. Seliga

Alessio Peracchi

Arthur J. L. Cooper

Carole L. Linster

Emile Van Schaftingen

Jin Sun

Kay Huebner

Kenneth W. Ellens

Maria Veiga-da-Cunha

Nicole Paczia

Simon Marlaire

Stephane Jaisson Guido T. Bommer

Tomiko Kuhara

Vincent Stroobant

English

Archivio istituzionale della Ricerca -  Università degli Studi di Parma

11 October 2022University of Parma Research RepositoryEnzymes that make and enzymes that fix mistakes: Nit1 is a ‘repair’ amidase that hydrolyzes deaminatedglutathione / Peracchi, Alessio; Veiga-da-Cunha, Maria; Kuhara, Tomiko; Ellens, Kenneth W.; Paczia,Nicole; Stroobant, Vincent; Seliga, Agnieszka K.; Marlaire, Simon; Bommer, Stephane Jaisson Guido T.;Sun, Jin; Huebner, Kay; Linster, Carole L.; Cooper, Arthur J. L.; Van Schaftingen, Emile. - ELETTRONICO. -(2017), pp. 37-38.OriginalEnzymes that make and enzymes that fix mistakes: Nit1 is a ‘repair’ amidase that hydrolyzes deaminatedglutathionePublisher:PublishedDOI:Terms of use:openAccessPublisher copyright(Article begins on next page)Anyone can freely access the full text of works made available as "Open Access". Works made availableAvailability:This version is available at: 11381/2887593 since: 2021-02-04T12:19:55ZSIBThis is the peer reviewd version of the followng article:37  SIB 2017 ______________________________________________________________________________________  Enzymes that make and enzymes that fix mistakes: Nit1 is  a   Alessio Peracchi1,2*, Maria Veiga-da-Cunha2, Tomiko Kuhara3, Kenneth W. Ellens4, Nicole Paczia4, Vincent Stroobant2, Agnieszka K. Seliga2, Simon Marlaire2, Stephane Jaisson2 Guido T. Bommer2, Jin Sun5, Kay Huebner5, Carole L. Linster4, Arthur J. L. Cooper6, Emile Van Schaftingen2  1 Dept. of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy; 2 de Duve Institute, Université Catholique de Louvain. Brussels, Belgium; 3 Japan Clinical Metabolomics Institute, Kahoku, Ishikawa, Japan; 4 Université du Luxembourg, Belvaux, Luxembourg; e Ohio State University, Columbus, OH, USA; h New York Medical College, Valhalla, NY, USA *Corresponding author:  alessio.peracchi@unipr.it  Enzymes of intermediary metabolism are not perfectly specific and tend to act on intracellular compounds resembling their true substrate. The products of such side reactions are non-classical metabolites, which in several cases need to be eliminated or recycled by specific enzymes, called metabolite repair enzymes 1, 2. The increasing rate at which repair enzymes are being discovered suggests that a might in fact be involved in metabolite repair. Here I will describe a study on the mammalian protein Nit1, whose enzymatic function has long remained a puzzle. Nit1 is highly conserved in eukaryotes and is thought to act as tumor suppressor. Despite being 35% sequence identical to -amidase (Nit2), it had been shown that Nit1 does not hydrolyze efficiently -ketoglutaramate (the known physiological substrate of Nit2). However, we demonstrated that both the mammalian Nit1 and its yeast ortholog can very efficiently hydrolize deaminated glutathione (dGSH), i.e., a form of glutathione in which the free amino group has been replaced by a carbonyl group. We further showed that Nit1-KO mutants of both human and yeast cells accumulate dGSH, and that the same compound is excreted in large amounts in the urine of Nit1-KO mice. Finally, we showed that several mammalian aminotransferases can form dGSH via a common (if slow) side-reaction, and provided indirect evidence that transaminases are mainly responsible for dGSH formation in cultured mammalian cells.  Altogether, these findings delineate a typical instance of metabolite repair, whereby the promiscuous activity of some abundant enzyme(s) of primary metabolism leads to the formation of a useless and 38  a useful metabolite. The need for a dGSH repair reaction does not seem limited to eukaryotes: we demonstrated that Nit1 homologs acting as excellent dGSH amidases also occur in Escherichia coli and other glutathione-producing bacteria 3.  References 1. C. L. Linster, E. Van Schaftingen and A. D. Hanson, Nat Chem Biol (2013) 9, 72-80. 2. E. Van Schaftingen, R. Rzem, A. Marbaix, F. Collard, M. Veiga-da-Cunha and C. L. Linster, J Inherit Metab Dis (2013) 36, 427-434. 3. A. Peracchi, M. Veiga-da-Cunha  et al. . Proc Natl Acad Sci U S A., (2017) 114, E3233-E3242.   

Enzymes that make and enzymes that fix mistakes: Nit1 is a ‘repair’ amidase that hydrolyzes deaminated glutathione

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Enzymes that make and enzymes that fix mistakes: Nit1 is a ‘repair’ amidase that hydrolyzes deaminated glutathione

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